Benzonaphthalene derivatives, a process for their preparation and their use in therapeutic and cosmetic compositions

ABSTRACT

A benzonaphthalene compound has the formula ##STR1## wherein R 1  represents (i) ##STR2## or (ii) --CH 2  OH; R 6  represents ##STR3## or OR 7  wherein R 7  represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r&#39; or r&#34; represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl or a residue of an amino acid or a sugar, or together form a heterocycle; R 2  represents hydrogen, alkyl having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic radical; R 3  represents hydrogen, hydroxy, alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic radical, a thiocycloaliphatic radical or --0--Si(CH 3 ) 2  --R 8  wherein R 8  represents lower alkyl; and R 4  and R 5  represent hydrogen, lower alkyl, hydroxy or lower acyloxy. 
     This compound is useful in the topical and systemic treatment of dermatologic diseases and in the treatment of the degeneration of conjuctive tissues. The compound also possesses anti-tumor acitivity.

This is a division of application Ser. No. 07803,965, filed Dec. 9,1991, now U.S. Pat. No. 5,183,889 which is a division of Ser. No.07502/122, filed Mar. 30, 1990, now U.S. Pat. No. 5,098,895, which is adivision of Ser. No. 07/120,968, filed Nov. 16, 1987, now U.S. pat. No.4,861,229, which is a division of Ser. No. 06/850,145, filed Apr. 10,1986, now U.S. Pat. No. 4,717,720.

The present invention relates to benzonaphthalene derivatives, to aprocess for preparing them and to their use in therapeutic and cosmeticcompositions.

These new benzonaphthalene derivatives are usefully employed in thetopical and systemic treatment of dermatological diseases linked tokeratinization disorders (differentiation--proliferation) anddermatological diseases, or others, with inflammatory and/orimmunoallergic components and in the treatment of diseases attributableto the degeneration of conjuctive tissue. The benzonaphthalenederivatives of the present invention also exhibit anti-tumor activity.Moreover, these derivatives can be employed in the treatment of atopy beit cutaneous or respiratory.

The benzonaphthalene derivatives of the present invention are alsousefully employed in the field of ophthalmology and principally in thetreatment of corneopathies.

A number of compounds have already been proposed for the varioustreatments noted above and principally compounds known under thedesignation of "retinoids" of which the most well-known ones are thetrans and cis retinoic acids (tretinoin and isotretinoin) andetretinate.

Compared to these known compounds, the benzonaphthalene derivativesaccording to the present invention exhibit a strong activity and betterstability to light and to oxygen of the air.

The benzonaphthane derivatives of the present invention can berepresented by the following formula: ##STR4## wherein

R₁ represents:

(i) ##STR5## or (ii) --CH₂ OH,

R₆ represents ##STR6## or --OR₇ wherein R₇ : represents hydrogen, alkylhaving 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' andr" represent hydrogen, lower alkyl, mono- or polyhydroxyalkyl, aryloptionally substituted or a residue of an amino acid or aminated sugaror r' and r" taken together form a heterocycle,

R₂ represents hydrogen, branched or straight chain alkyl having 1-15carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic group,

R₃ represents hydrogen, hydroxy, straight or branched chain alkyl having1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphaticgroup substituted or not, a thio-cycloaliphatic group or a group of theformula --O--Si(CH₃)₂ --R₈ wherein R₈ represents linear or branchedlower alkyl,

R₄ and R₅ each independently represent hydrogen, lower alkyl, hydroxy ora lower acyloxy group, and the salts of the said benzonaphthalenederivatives of Formula I.

By the expression "lower alkyl" is meant alkyl radicals having from 1-6carbon atoms and principally methyl, ethyl, isopropyl, butyl andtert.butyl.

The term "alkoxy" is intended to include radicals having 1-10 carbonatoms and principally methoxy, ethoxy, isopropoxy, hexyloxy and decyloxyradicals.

By the expression "lower acyloxy" is meant radicals having 1-4 carbonatoms and principally acetyloxy and propionyloxy radicals.

By the term "monohydroxyalkyl" is meant a monohydroxy substitutedradical having 2 or 3 carbon atoms, principally, 2-hydroxy ethyl and2-hydroxypropyl.

Representative residues of aminated sugars include those derived fromglucosamine, galactosamine and mannosamine.

By the term "polyhydroxyalkyl" is meant an alkyl radical having 3-6carbon atoms substituted 2-5 hydroxyl groups, such as 2,3-dihydroxypropyl, 1,3-dihydroxy propyl, or the residue of pentaerythritol.

The term "cycloaliphatic" is meant to include a mono or polycyclicradical such as, for example, 1-methyl cyclohexyl or 1-adamantyl.

The preferred thiocycloaliphatic radical is, principally,1-adamantylthio.

When r' and r" together form a heterocycle, it is preferably apiperidino, piperazino, morpholino or pyrrolidino radical.

The preferred compounds of Formula I are more particularly those havingthe following formula: ##STR7## wherein

R'₆ represents ##STR8## or --OR'₇,

r' and r" each independently represent hydrogen or lower alkyl, or r'and r" taken together form a morpholino radical,

R'₇ represents hydrogen or lower alkyl,

R'₂ represents hydrogen, alkyl, alkoxy or l-adamantyl, and

R'₃ represents hydrogen, hydroxy, alkyl, alkoxy or 1-adamantylthio.

Representative compounds of the present invention include:

(1) 6-(3-methylphenyl)-2-naphthoic acid and its methyl ester,

(2) 6-(4-tert.butyl phenyl)-2-naphthoic acid and its methyl ester,

(3) 6-(3-tert.butyl phenyl)-2-naphthoic acid and its methyl ester,

(4) 6-(3,4-dimethoxy phenyl)-2-naphthoic acid and its methyl ester,

(5) 6-[p-(1-adamantylthio)phenyl]-2-naphthoic acid and its methyl ester,

(6) 6-[3-(1-adamantyl)-4-methoxyphenyl-2-naphthoic acid and its methylester,

(7) the methyl ester of6-[3-(1-adamantyl)-4-tert.butyldimethylsilyloxyphenyl]-2-naphthoic acid,

(8) the methyl ester of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoicacid,

(9) 6-[3-(1-adamantyl-4-hydroxyphenyl]-2-naphthoic acid,

(10) the methyl ester of6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid,

(11) 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid,

(12) the methyl ester of6-[3™(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid,

(13) 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid,

(14) the methyl ester of6-[3-(1-adamantyl)-4-methoxyphenyl]-4-acetoxy-1-methyl-2-naphthoic acid,

(15) 6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy 1-methyl-2-naphthoicacid,

(16) the methyl ester of6-[3-(1-adamantyl)-4-methoxy-phenyl]-4-hydroxy-1-methyl-2-naphthoicacid,

(17) the methyl ester of6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid,

(18) 6-[3-(1-adamantyl)-4-methoxypheny1]-1-methyl-2-naphthoic acid,

(19) 6-[3-(1-adamantyl 4-methoxyphenyl]-2-naphthalene methanol,

(20) the ethylamide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoicacid,

(21) the morpholide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoicacid,

(22) the methyl ester of 6-[3-tert.butyl-4-methoxyphenyl]-2-naphthoicacid,

(23) 6-(3-tert.butyl-4-methoxyphenyl)-2-naphthoic acid,

(24) the methyl ester of6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid, and

(25) 6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid.

The present invention also relates to a process for preparing thecompounds of Formula I.

According to this process the compounds of Formula I are obtained by acoupling reaction between a halogenated compound of Formula III and ahalogenated derivative of naphthalene of Formula IV: ##STR9## wherein

R₁ to R₅ have the same meanings as those given above for Formula I and

X and Y represent Cl, Br, F or I.

According to this coupling reaction, the halogenated compound of FormulaIII is transformed into its magnesium, lithium or zinc form inaccordance with methods described in the literature and is coupled withthe halogenated naphthalene derivative of Formula IV by employing, as areaction catalyst, a transition metal or one of its complexes.

Particularly preferred catalysts are those derived from nickel orpalladium and more particularly the compounds of Ni_(II) (NiCl₂) withvarious phosphines.

The coupling reaction is generally carried out at a temperature between-20° and +30° C. in an anhydrous solvent such as, for example,dimethylformamide or tetrahydrofuran.

The resulting product can be purified by recrystallization or silicacolumn chromatography.

Obviously, the choice of the halogenated naphthalene derivative ofFormula IV, for use in the coupling reaction with the halogenatedcompound of Formula III, must be such that it can lead, by subsequentreaction, to the various meanings of the R₁ radical given above.

When the compounds according to the present invention are provided insalt form, it is a question of salts of an alkali or alkaline earthmetal or of an organic amine when the compounds have at least one freeacid function.

The present invention also relates to a medicinal composition comprisingas the active principle thereof the compounds of Formula I as definedabove.

These compounds exhibit excellent activity in the test for inhibitingornithine decarboxylase after induction, by "tape stripping" the body ofa nude rat. This test is considered a measure of the activity of theretinoids with regard to cellular proliferation phenomenon.

For instance, it has been noted that in this test,6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid exhibits aneffective dose between 5 and 25 nmoles applied per cm².

The compounds according to the invention also exhibit a strong activityin the differentiation test of embryonic tetracarcinoma F9 rat cells(Cancer Research 43, page 5268, 1983).

As an illustration, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoicacid, at a 0.01 micromolar concentration induces the differentiation ofF9 carcinoma cells in endoderm cells.

6-(3-tert.butyl phenyl)-2-naphthoic acid acts in the same fashion at aconcentration of 1 micromolar.

Moreover, the irritation test carried out on a rabbit has shown that thecompounds of Formula I are less irritating than known retinoids ofanalogous structure. Moreover, their acute toxicity is weaker.

The compounds of the present invention are indeed particularly suitablefor the treatment of dermatological diseases linked to a keratinizationdisorder (differentiation, proliferation), as well as dermatologicaldiseases or others with inflammatory and/or immunoallergic componentssuch as principally:

acne vulgaris, comedons or polymorphs, solar acne seniles andmedicamental or professional acne;

extensive and/or severe forms of psoriasis, and other keratinizationdisorders, and principally ichtyosis and ichtyosiform states;

Darier disease;

palmo-plantary keratodermy;

leucoplasies and leucoplasiform states, lichen plan;

all dermatological proliferations, benign or malignant, severe orextended.

They are also active for certain rheumatic diseases principallypsoriasic rheumatism, for cutanerus or respiratory atopies, as well asfor certain ophthalmologic disorders relative to the corneopathies.

The present invention also relates to medicinal compositions containingat least one compound of Formula I, as defined above and/or a saltthereof.

The present invention thus relates to a new medicinal composition,intended principally for the treatment of the above-mentioned diseases,comprising in a pharmaceutically acceptable support, at least onecompound of Formula I and/or a salt thereof.

As has been indicated previously, the berzonaphthalene derivativesaccording to the present invention, relative to known retinoids, exhibitbetter stability against light and oxygen, this being essentially due tothe fact that they do not possess any easily isomerized double bonds.

The compounds according to the present invention are generallyadministered at a daily dosage of about 2 μg/kg to 2 mg/kg of bodyweight.

As vehicles or supports for these compositions, there can be employedany conventional support, the active compound being found either in thedissolved state or in the dispersed state in the vehicle or support.

The composition can be administered enterally, parenterally, topicallyor ocularly. When administered enterally, the medicinal composition canbe provided in the form of tablets, gelules, lozenges, syrups,suspension, solutions, powders, granules or emulsions. When administeredparenterally the medicinal composition can be provided in the form ofsolutions or suspensions for perfusion or injection.

When administered topically, the pharmaceutical compositions based onthe compounds in accordance with the present invention can be providedin the form of ointments, tinctures, creams, pommades, powders,impregnated pads, buffers, solutions, lotions, gels, sprays or evensuspensions.

These compositions for topical application or administration can beprovided either under anhydrous form, or in aqueous form according toclinical indications. When administered ocularly, the compositions areprincipally eyewashes.

The topical or ocular composition contains preferably between 0.0005 and5 weight percent of the active compound based on the total weight of thecomposition.

The compounds of Formula I, according to the present invention also finduse in the cosmetic field, in particular in body and hair hygiene andprincipally for acne, hairgrowth, preventing hair fallout, to combatagainst the oily appearance of the skin or hair, in the protectionagainst harmful effects of the sun or in the treatment ofphysiologically dry skin.

The present invention then also envisages a cosmetic compositioncontaining in a cosmetically acceptable support at least one compound ofFormula I and/or a salt thereof, this composition being providedprincipally in the form of a lotion, gel, soap or shampoo.

The concentration of the compound(s) of Formula I in the cosmeticcompositions is between 0.0005 and 2 weight percent, preferably between0.01 and 1 weight percent, based on the total weight of the composition.

The medicinal and cosmetic compositions according to the presentinvention can contain inert or even pharmacodynamic or cosmeticallyactive adjuvants and principally: hydrating agents such asthiamorpholinone and its derivatives or urea; antiseborrheic agents suchas S-carboxymethylcysteine, S-benzyl cysteamine and their derivatives,or tioxolone; antibiotics such as erythromycin, neomycin or thetetracyclines; agents favoring hair growth such as "Minoxidil"(2,4-diamino-6-piperidinopyrimidine-3-oxide) and its derivatives,Diazoxide and Phenytoin; steroidal anti-inflammatory agents; carotenoidsand principally β-carotene; and antipsoriasic agents such as anthralinand its derivatives, 5,8,11,14-eicosatetrainoic acid and 5,8,11-triynoicacid.

The compositions according to the present invention can also containflavor improving agents, preservatives, stabilizers, humidity regulatingagents, pH regulating agents, osmotic pressure modifying agents,emulsifiers, UV-A and UV-B filters and antioxidants such asα-tocopherol, butylhydroxy anisole or butylhydroxy toluene.

The following non-limiting examples illustrate several examples for thepreparation of the active compounds of Formula I according to thepresent invention, as well as examples of compositions containing theseactive compounds.

EXAMPLE 1 Methyl ester of 6-(3-methylphenyl)-2-naphthoic acid. Compoundof Formula II wherein R'₃ =H and R'₂ =--CH₃ and R'₆ =--OCH₃

342 mg (2 mmol) of 3-bromotoluene in 4 ml of THF are converted into thecorresponding magnesium form and then treated with an equivalent of zincchloride to provide the corresponding zinc derivative. There aresuccessively added 310 mg (1.17 mmol) of methyl 6-bromo-2-naphthoate and10 mg (0.02 mmol) of NiCl₂ /1,2-(diphenylphosphino)ethane--DPPE--as thecatalyst. The reaction mixture is stirred at ambient temperature for 30minutes and the mineral salts are then removed by passing the reactionmixture through a 2 × 3 cm silica column. The reaction mixture is thenevaporated to dryness and the residue is chromatographed (HPLCcolumn--Zorbax sil), using as the eluant, a mixture of cyclohexane (75%)and ether (25%). The product thus recovered has an Rf=0.45 (silicaplate, eluant: hexane 50%, dichloromethane 50%) and crystallizes onevaporation of the chromatography solvents. The yield is 84%. Meltingpoint--107° C.

EXAMPLE 2 Methyl ester of 6-(4-tert.butyl phenyl)-2-naphthoic acid.Compound of Formula II wherein R'₂ =H, R'₃ =--C(CH₃)₃ and R'₆ =--OCH₃

In a manner analogous to Example 1, starting with 639 mg (3.0 mmol) of4-bromo tert.butyl benzene and 465 mg (1.75 mmol) of methyl6-bromo-2-naphthoate, 0.30 g of the expected product is obtained.Yield--54%. Melting point--154° C.

EXAMPLE 3 Methyl ester of 6-(3-tert.butyl phenyl)-2-naphthoic acid.Compound of Formula II wherein R'₃ =H, R'₂ =--C(CH₃)₃ and R'₆ =--OCH₃

3.50 g (16.4 mmol) of 3-tert.butyl bromotenzene are added to asuspension of magnesium (0.44 g --18 m Atg) in 20 ml of drytetrahydrofuran. The reaction is initiated by addition of an iodinecrystal and continued at 50° C. for 30 minutes.

2.46 g (18 mmol) of anhydrous zinc chloride dissolved in 20 ml of drytetrahydrofuran are then added and after 15 minutes, the reactionmixture is cooled to 0° C. At this point, 3.63 g (13.7 mmol) of methyl6-bromo-2-naphthoate and 86 mg (0.26 mmol) of the NiCl₂ /DPPE complexare added to the reaction mixture.

After stirring for 1 hour at ambient temperature, 100 ml of water areadded and the mixture is extracted with ether. After washing the organicphase with a saturated solution of sodium bicarbonate, and water, thendrying (sodium sulfate) and evaporating the solvents, the resultingresidue is recrystallized in heptane. 3.12 g of the methyl ester of6-(3-tert.butyl phenyl)-2-naphthoic acid which melts at 138° C. areobtained.

EXAMPLE 4 6-(3-tert.butyl phenyl)-2-naphthoic acid. Compound of FormulaII wherein R'₃ =H, R'₂ =--C(CH₃)₃ and R'₆ =OH.

1.0 g (3.14 mmol) of the methyl ester of 6-(3-tert.butylphenyl)-2-naphthoic acid obtained in Example 3 is added to a mixture of95% ethanol (40 ml) and soda (4 ml, 5N).

The mixture is heated at 60° C. for 2 hours at which point 50 ml ofwater are added and the mixture is acidified to pH 1 with 2N HCl. Theacidified mixture is then extracted with ether and the organic phase iswashed with water until neutral. After drying (sodium sulfate) andevaporation of the solvent, 6-(3-tert.butyl phenyl)-2-naphthoic acid(900 mg) which sublime 190° C. is obtained.

EXAMPLE 5 Methyl ester of 6-[p-(1-adamantylthio)phenyl]-2-naphthoicacid. Compound of Formula II wherein R'₂ =H, R'₃ =1-adamantylthio andR'₆ =--OCH₃

(a) p-(1-adamantylthio) bromobenzene.

3.78 g (20 mmol) of p-bromothiophenol, 3.04 g (20 mmol) of 1-adamantanoland 10 ml of trifluoroacetic acid are stirred at ambient temperature for8 hours and then poured into water. Sodium bicarbonate is added untilthe mixture is neutral at which time it is extracted with methylenechloride. The organic phase is dried and evaporated. Afterrecrystallization in isooctane, 5.9 g of the expected product areobtained. Yield--92%. Melting point: 121°-122° C.

(b) Methyl ester of 6-[p-(1-adamantylthio)phenyl]-2-naphthoic acid

0.64 g (26.5 m Atg) of magnesium suspended in 10 ml of tetrathydrofuran(THF) are treated slowly with 5.7 g (17.6 mmol) of p-(1-adamantylthio)bromobenzene. After heating at reflux for 2 hours and cooling to 20° C.,2.4 g (17.6 mmol) of anhydrous Zn Cl₂ are added. The mixture is stirredfor one hour at 20° C. at which point 2.8 g (10.4 mmol) of methyl6-broxo-2-naphthoate are added and then 92 mg of NiCl₂/1,2-(diphenylphosphino)ethane-DPPE complex are added.

The mixture is stirred at ambient temperature for 2 hours, poured intowater, extracted with methylene chloride, washed with sodiumbicarbonate, dried and then evaporated. The residue is recrystallized ina mixture of diisopropyl oxide and ethyl acetate. 3.7 g of the expectedproduct are obtained. Yield--84%. Melting point: 189°-190° C.

EXAMPLE 6 6-[p-(1-adamantylthio)phenyl]-2-naphthoic acid.

Compound of Formula II wherein R'₂ =H, R'₆ =OH and R'₃ =1-adamantylthio

3 g (7 mmol) of the ester obtained in Example 5(b) are treated with asolution of soda in methanol (150 ml, 5N). The reaction mixture isheated at reflux for 12 hours, evaporated, taken up in water andacidified with concentrated HCl. The resulting solid is filtered anddried under a vacuum on phosphoric anhydride. The resulting white solidis pulverized in methanol at reflux, cooled and filtered. 2.5 g of theexpected product are thus obtained. Yield--86%. Melting point: 334°-336°C.

EXAMPLE 7 Methyl ester of 6-(3,4-dimethoxy phenyl)-2-naphthoic acid.Compound of Formula II wherein R'₂ =R'₃ =R'₆ =--OCH₃.

0.93 g (38.3 mAtg) of magnesium in 20 ml of THF are slowly treated with5.5 g (25.5 mmol) of 4-bromoveratrole. At the end of the addition, themixture is heated at reflux for two hours, and then cooled. At thispoint 3.48 g (25.5 mmol) of anhydrous ZnCl₂ are added and the mixture isstirred one hour at ambient temperature. 3.98 g (15 mmol) of methyl6-bromo-2-naphthoate are then added followed by the addition of 130 mgof NiCl₂ /DPPE complex. The mixture is stirred for two hours a ambienttemperature and then poured into water and extracted withdichloromethane. The organic phase is dried and evaporated. The residueis recrystallized in a mixture of isopropyl ether and ethyl acetate. 3.4g of the expected product are obtained. Yield--70%. Melting point:147°-148° C.

EXAMPLE 8 6-(3,4-dimethoxyphenyl-2-naphthoic acid. Compound of FormulaII wherein R'₂ =R'₃ =--CCH₃ and R'₆ =OH

2.6 g (8 mmol) of the ester obtained in example 7 are treated with asolution of soda in methanol (200 ml, 2N). The reaction mixture isheated at reflux for 8 hours, evaporated, taken up in water, acidifiedwith concentrated HCl, and filtered. The solid thus obtained is driedunder a vacuum (on P₂ O₅). The resulting white solid is pulverized inmethanol at reflux, cooled and then filtered. 2.3 g of the expectedproduct are obtained. Yield--92%. Melting point: 241°-243° C.

EXAMPLE 9 Methyl ester of 6-[3-(1-adamantyl)-4 methoxyphenyl]-2-naphthoic acid. Compound of Formula II wherein R'₃ --OCH₃, R'₂=1-adamantyl and R'₆ =OCH₃

(a) 2-(1-adamantyl)-4-bromophenol.

34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of1-adamantanol are dissolved in 100 ml of dichloromethane. To theresulting solution there are slowly added 10 ml of concentrated sulfuricacid. The mixture is stirred for 8 hours at ambient temperature, pouredinto water, neutralized with sodium bicarbonate, extracted withmethylene chloride, dried and evaporated. After recrystallization inisooctane 52.8 g of the expected product are obtained. Yield--86%.Melting point: 140°-141° C.

(b) 2-(1-adamantyl)-4-bromoanisole.

To a suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50ml of THF, there are slowly added, while maintaining the temperature at20° C., 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixtureis stirred for 1 hour at ambient temperature at which point 9 ml (144mmol) of methyl iodide are added. The mixture is then stirred for 2hours at 20° C. poured into water, extracted with ether, dried andevaporated. The product is purified by passage through a silica column(10 × 30 cm), eluting with a mixture of hexane (90%) and dichloromethane(10%). On evaporation, 26.2 g of a white solid are obtained. Yield--68%.Melting point: 138°-139° C.

(c) Methyl ester of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoicacid.

To a suspension of magnesium (1.64 g, 67.5 m Atg) in 30 ml of THF, thereis added a solution of 1.4 g (4.5 mmol) of2-(1-adamantyl)-4-bromoanisole and 0.39 ml of dibromoethane in 10 ml ofTHF. The mixture is stirred until the reaction is initiated and thenthere is slowly added a solution of 13.1 g (40.8 mmol) of2-(1-adamantyl)-4-bromoanisole in 90 ml of THF. The mixture is heated atreflux for 2 hours, and then cooled to 20° C. There are then added 6.2 g(45 mmol) of anhydrous ZnCl₂. The mixture is stirred for 1 hour at 20°C. at which point 7.95 g (30 mmol) of methyl 6-bromo-2-naphthoate areadded followed by the addition of 300 g of NiCl₂ /DPPE complex. Themixture is stirred again for 2 hours at 20° C., poured into water,extracted with CH₂ Cl₂, dried and evaporated. The product is isolated bycolumn chromatography, eluting with a mixture of heptane (70%) anddichloromethane (30%) and then recrystallized in ethyl acetate. 12.2 9of the expected product are obtained. Yield--78%. Melting point:222°-223° C.

EXAMPLE 10 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid.Compound of Formula II wherein R'₃ =OCH₃, R'₂ =1-adamantyl and R'₆ =OH.

10.5 g of the ester obtained in Example 9(c) are treated with a solutionof soda in methanol (200 ml, 4.2 N). The mixture is heated at reflux for48 hours. The solvents are evaporated and the resulting residue is takenup in water and acidified with concentrated HCl. The solid is filteredand dried under a vacuum over phosphoric anhydride.

The resulting white solid is recrystallized in a mixture of THF andethyl acetate. 8.2. g of the expected product are obtained. Yield--81%.Melting point: 325°-327° C.

EXAMPLE 11 Methyl ester of 6-[3-(1-adamantyl)-4-tert.butyldimethylsilyloxylphenyl]-2-naphthoic acid. Compound of Formula I whereinR₄ =R₅ =H, R₂ =1-adamantyl, R₃ =OSi(CH₃)₂ C₃ H₇ and ##STR10##

(a) 2-(adamantyl)-4-bromo-1-tert.butyldimethylsilyloxybenzene.

30.7 g of 2-adamantyl-4-bromophenol (100 mmol) are dissolved in DMF (200ml). There are then added triethylamine (15.4 ml, 110 mmol) and4-N,N-dimethylaminopyridine (DMAP, 500 mg,4 mmol).

To the resulting solution there is slowly added a solution oftert.butyldimethylsilyl chloride (15.7 g, 104 mmol) in DMF (100 ml). Themixture is stirred at ambient temperature for 4 hours, poured intowater, extracted with ether, dried (MgSO₄) and evaporated. The residueis dissolved in hexane and purified by passage through a silica column(eluant: hexane). 36.2 g (86%) of2-adamantyl-4-bromo-1-tert.butyldimethylsilyloxybenzene are obtained.Melting point: 111° C.

(b) Methyl ester of6-[3-(1-adamantyl)-4-tert.butyldimethylsiloxyphenyl]-2-naphthoic acid.

33.3 g (79 mmol) of the compound produced in part (a) above, dissolvedin 200 ml of THF are slowly added to a suspension of magnesium (2.9 g,118 Atg) in 60 ml of THF. Once the addition is complete, the mixture isheated at reflux for 2 hours at which point the temperature of themixture is permitted to return to ambient temperature. 10.8 g (79 mmol)of anhydrous zinc chloride are added and the mixture is stirred for onehour at ambient temperature, at which point 10.5 g (39.5 mmol) of methyl6-bromo-2-naphthoate and 500 mg of NiCl₂ /DPPE complex are added. Thismixture is then stirred for 2 hours at ambient temperature, poured intowater, extracted with CH₂ Cl₂, dried and evaporated. The residue ischromatographed on a silica column (eluant: mixture of heptane (70%) andether (30%). 18.5 (90%) of the methyl ester of 6-[3-(1-adamantyl)-4™tert.butyldimethylsilyloxyphenyl]-2-naphthoic acid are obtained.Melting point: 152°-153° C.

EXAMPLE 12 Methyl ester of6[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid. Compound of FormulaI wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =OH and R₁ =COOCH₃

17.5 g (33 mmol) of the ester produced in Example 11 are dissolved in300 ml of THF. To this solution there is added 36.6 ml of a molarsolution of tetrabutylammonium fluoride in THF. The mixture is stirredfor 2 hours at ambient temperature, poured into water and extracted withCH₂ Cl₂. The organic phase is recovered, dried (MgSO₄), and the solventsevaporated. The resulting residue is recrystallized in a mixture ofethylacetate (70%) and THF (30%) to give the expected ester. 11 g (81%).Melting point: 266° C.

EXAMPLE 13 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid.Compound of Formula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =OH and R₁=COOH.

5 g (12 mmol) of the ester obtained in Example 12 are treated with 200ml of methanolic soda (2N), under nitrogen, for 8 hours. The solventsare evaporated and the residue taken up in water and acidified to pH 1(concentrated HCl). The reaction mixture is filtered, washed with water,the solid product is extracted with ethyl ether, dried (MgSO₄) andevaporated. The residue is recrystallized in isopropylether, yielding3.8 g (79%) of the expected acid. Melting point: 270°-271° C.

EXAMPLE 14 Methyl ester of6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid. Compound ofFormula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =--OC₁₀ H₂₁ and R₁=COOCH₃

(a) 2-(1-adamantyl)-4-bromo-1-decyloxy benzene.

To a suspension of sodium hydride (80% in oil, 3.2 g, 104 mmol) in 100ml of THF, there is slowly added a solution of2-(1-adamantyl)-4-bromophenol (29 g, 95 mmol) in 200 ml of THF. Themixture is stirred until the evolution of gas ceases at which point 27.8g (23 ml, 104 mmol) of 1-iododecane and 100 ml of DMF are added. Themixture is stirred for 12 hours at ambient temperature, poured intowater, extracted with ether, dried and the solvents evaporated. Theresulting residue is purified by passage through a silica column(eluant: heptane), yielding 40.7 g (96%) of2-(1-adamantyl)-4-bromo-1-decyloxybenzene. Melting point: 69°-70° C.

(b) Methyl ester of 6-[3-(1-adamantyl)™4-decyloxyphenyl]-2-naphthoicacid.

In a manner analogous to Example 9c, starting with 17.9 g (40 mmol) ofthe brominated derivative obtained in part (a) above, and 5.3 g ofmethyl 6-bromo-2-naphthoate, 7.4 g (67%) of the expected ester areobtained. Melting point: 113°-114° C.

EXAMPLE 15 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid.Compound of Formula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =--OC₁₀ H₂₁and R₁ =COOH

6.3 g (11 mmol) of the ester obtained in Example 14 dissolved in 200 mlof THF are treated at reflux with 200 ml of 2M methanolic soda for 4hours. The solvents are evaporated and the residue is taken up in water,acidified to pH 1 (concentrated HCl), filtered, washed with water andthe solid is extracted with ether. The extract is dried and the solventevaporated. The resulting residue is treated with 700 ml of ethylacetate at reflux. On cooling 5.9 g (97%) of the expected acid areobtained. Melting point: 214°-215° C.

EXAMPLE 16 Methyl ester of6-[3-(1-adamantyl)-4-hexyloxy-phenyl]-2-naphthoic acid. Compound ofFormula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =--OC₆ H₁₃ and R₁=--COOCH₃

5.3 g (13 mmol) of the ester obtained in Example 12 are dissolved in 100ml of DMF and added to a suspension of NaH (80% in oil; 0.46 g; 15.4mmol) in DMF (50 ml). The mixture is stirred at ambient temperatureuntil the evolution of gas ceases, at which point 1-iodohexane (3.26 g;2.3 ml; 15.4 mmol) is added. This mixture is then stirred for 4 hours atambient temperature, poured into water, extracted with ether, dried andevaporated. The residue is purified by passage through a silica column(eluant: mixture of dichloromethane--50% and hexane--50%), thenrecrystallized in isooctane to give 5.5 g (87) of the expected pureproduct. Melting point: 129°-130° C.

EXAMPLE 17 6-[3-(1-adamantyl)-4-hexyloxypheryl]-2-naphthoic acid.Compound of Formula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =--OC₆ H₁₃and R₁ =--COOH

In a manner analogous to Example 15, starting with 4.2 g (8.4 mmol) ofthe ester obtained in Example 16, 3.8 g (95%) of6-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid are obtained. Meltingpoint: 260°-261° C.

EXAMPLE 18 Methyl ester of 6-[3-(1-adamantyl)-4-methoxyphenyl]-4-acetoxy-1-methyl-2-naphthoic acid. Compound of Formula Iwherein R₄ =CH₃, R₅ =--OCOCH₃, R₂ =1-adamantyl, R₃ =--OCH₃ and R₁=--COOCH₃

47.6 g (148 mmol) of 2-(1-adamantyl)-4-bromoanisole and 13.9 g (6.3 ml,74 mmol) of dibromoethane, dissolved in 100 ml of THF are added slowlyto a suspension of magnesium (5.4 g, 222 mmol) in the THF (1000 ml). Themixture is brought to reflux for 2 hours at which point zinc chloride(20.2 g, 148 mmol) is added. The mixture is stirred for 1 hour and thereare successively added 24.9 g (74 mmol) of methyl4-acetoxy-6-bromo-1-methyl-2-naphthoate and 500 mg of NiCl₂ DPPEcomplex. This mixture is stirred for 8 hours at ambient temperature,poured into a saturated aqueous solution of ammonium chloride, extractedwith CH₂ Cl₂, dried and the solvents evaporated. The resulting residueis purified by passage through a silica column (eluant: mixture ofhexane, 40%, and CH₂ Cl₂, 60%). The resulting product is recrystallizedin isopropyl ether, yielding 23.5 g (64%) of the expected ester. Meltingpoint: 201°-202° C.

EXAMPLE 196-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic acid.Compound of Formula I wherein R₄ =CH₃, R₅ =OH, R₂ =1-adamantyl, R₃ =OCH₃and R₁ =COOH

23 g (46 mmol) of the ester obtained in Example 18 are treated at refluxfor12 hours with 300 ml of methanolic soda (2N). The solvents areevaporated and the residue is taken up in water and acidified to pH 1(concentrated HCl). The solid is filtered, washed with water, dissolvedin ethyl ether, dried (MgSO₄) and evaporated. The resulting residue isrecrystallized in ethyl acetate to give 18.7 g (92%) of the expectedacid. Melting point: 281°-283° C.

EXAMPLE 20 Methyl ester of6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic acid.Compound of Formula I wherein R₄ =CH₃, R₅ =OH, R₂ =1-adamantyl, R₃ =OCH3and R₁ =COOCH₃

17 g (38 mmol) of the acid obtained in Example 19 are treated for 12hours at reflux with 200 ml of methanol containing 2 ml of sulfuricacid. The solvents are evaporated and the residue is taken up in water,extracted with ether, dried and evaporated. The residue is purified bypassage through a silica column using as the eluant a 90:10 mixture ofether/THF. The product is recrystallized in ethyl acetate to obtain theexpected pure ester --15 g (86%). Melting point: 272°-274° C.

EXAMPLE 21 Methyl ester of6-[3-(1-adamantyl)-4-methoxy-phenyl]-1-methyl-2-naphthoic acid. Compoundof Formula I wherein R₄ =CH₃, R₅ =H, R₂ =1-adamantyl, R₃ =OCH₃ and R₁=--COOCH₃

(a) Methyl6-[3-(1-adamantyl)-4-methoxyphenyl]-4-dimethylaminothiocarbonyloxy-1-methyl-2-naphthoate.

4.56 g of the ester obtained in Example 20, dissolved in THF (100 ml)are slowly added to a suspension of sodium hydride (80% in oil, 360 mg,12 mmol) in DMF (50 ml). The mixture is stirred for 1 hour at ambienttemperature and then for 1 hour at 40° C. There are then added 1.75 g(14 mmol) of dimethylthiocarbamoyl chloride, and the mixture is stirredinitially at ambient temperature for 2 hours and then at 40° C. for 2hours. The reaction mixture is poured into water, extracted with ether,dried, and the solvents evaporated. The product is purified by passagethrough a silica column (eluant: CH₂ Cl₂), yielding 4 g (74%) of theexpected intermediate product. Melting point: 137°-138° C.

(b) Methyl6-[3-(1-adamantyl)-4-methoxyphenyl]-4-dimethylcarbonythio-1-methyl-2-naphthoate.

3.8 g (7 mmol) of the ester obtained above in part (a) are heated undernitrogen at 260° C. for 0.5 hour. The residue is taken up in methylenechloride and purified by passage through a silica column (eluant: CH₂Cl₂). The resulting gum is taken up in isopropyl ether, yielding 3.3 g(87%) of the desired intermediate. Melting point: 201°-202° C.

(c) Methyl ester of6-[3-(1-adamantyl)-4.methoxyphenyl]-1-methyl-2-naphthoic acid.

The intermediate obtained above in part b) - (11 g, 20 mmol) isdissolved in 500 ml of ethanol. 20 g of Raney nickel are added and thereaction mixture is heated at reflux for 4 hours. 20 g of nickel arethen added and the mixture is heated again for 1 hour, at which pointthe mixture is cooled, concentrated and taken up in CH₂ Cl₂ (1000 ml).The precipitate is filtered and the filtrate is recovered, dried andevaporated. The product is purified by passage through a silica column(eluant: CH₂ Cl₂) and recrystallized in a mixture of ethyl acetate (90%)and THF (10%), yielding 8 g (90%) of the methyl ester of6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid. Meltingpoint: 238°-239° C.

EXAMPLE 22 6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoicacid. Compound of Formula I wherein R₄ =CH₃, R₅ =H, R₂ =1-adamantyl, R₃=OCH3 and R₁ =COOH.

6.8 g (15.4 mmol) of the ester obtained in Example 21(c) are treated asin Example 10 to give 5.8 g (88%) of the corresponding acid. Meltingpoint: 300°-302° C.

EXAMPLE 23 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene methanol.Compound of Formula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =OCH₃ andR₁ =--CH₂ OH

1.3 g (3 mmol) of the ester obtained in Example 9 dissolved in THF (5ml) are treated with 171 mg (4.5 mmol) of LiAlH₄. The mixture is heatedat reflux, cooled and treated with a saturated aqueous solution of thedouble tartrate of sodium and potassium. The reaction mixture isfiltered, evaporated to dryness, and the residue is recrystallized incyclohexane, yielding 1.0 g (83%) of the6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene methanol. Meltingpoint: 163°-164° C.

EXAMPLE 24 Ethylamide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoicacid. Compound of Formula I wherein R₄ =R₅ =H, R₂ =1-adamantyl, R₃ =OCH₃and R₁ =--CONHC₂ H₅.

(a) 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid chloride.

4.75 g (1.15 mmol) of the acid obtained in Example 10 in 200 ml ofdichloromethane are treated with 2.08 g (2.3 ml, 1.15 mmol) ofdicyclohexamine. The mixture is stirred at ambient temperature untildissolution. The solvents are evaporated and the residue taken up inether. The solid thus formed is filtered (6.8 g) and then taken up inmethylene chloride (50 ml). 1.37 g (0.84 ml, 1.15 mmol) of thionylchloride are added. The salt formed is filtered and the filtrate isrecovered, evaporated and dried. The resulting solid (3.9 g) is used assuch in the following step.

(b) Ethylamide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.

1.3 g (3 mmol) of the acid chloride produced in (a) above are dissolvedin 20 ml of THF. 405 mg (600 μl, 9 mmol) of ethylamine are added and themixture is stirred for 2 hours at ambient temperature. The mixture isthen poured into water, extracted with CH₂ Cl₂, dried and evaporated.The residue is recrystallized in ethyl acetate, yielding 1.1 g (85%) ofthe expected ethylamide. Melting point: 220°-221° C.

EXAMPLE 25 Morpholide of 6-[3-(1-adamantyl]-4-methoxyphenyl]-2-naphthoicacid.

In a manner analogous to Example 24, starting with 1.3 g of acidchloride produced in part (a) of Example 24 and 780 mg (780 ml, 9 mmol)of morpholine, there are obtained 1.3 g (91%) of the expectedmorpholide. Melting point: 212°-213° C.

EXAMPLE 26 Methyl ester of 6-[3-tert.butyl-4-methoxy phenyl]-2-naphthoicacid. Compound of Formula II wherein R'₂ =tert.butyl, R'₃ =R'₆ =OCH₃.

(a) 4-bromo-2-tert.butyl anisole.

3.10 g (22.6 mmol) of aluminum chloride are added all at once to amixture of 63.5 g (339 mmol) of p-bromoanisole and 31.4 g (330 mmol) oftert.butyl chloride. The mixture is stirred at ambient temperature untilthe evolution of gas ceases (about 15 minutes). The mixture is thenheated at 80° C. for 15 minutes and poured into ice. 300 ml of water areadded and the mixture is extracted with ether.

The organic phase is dried (MgSO₄), the solvents evaporated and theresidue purified by chromatography on a silica column (eluant: mixtureof methylene chloride--10% and hexane--90%). After evaporation of thesolvents, 4-bromo-2-tert.butyl anisole under the form of a colorless oilwhich crystallized on cooling is obtained. 31.9 g (39%).

(b) Methyl ester of 6-[3-tert.butyl-4-methoxy phenyl]-2-naphthoic acid.

There is slowly added, drop by drop, a solution of 18.8 g (77 mmol) of4-bromo-2-tert.butyl anisole to 2.26 g (93 mmol) of magnesium turningsand a crystal of iodine. The mixture is heated until the Grignard beginsto form, at which point the remainder of the solution containing thebrominated derivative is poured in a manner to maintain a regularreflux. Once the addition is complete, the mixture is heated at 40° C.for 30 minutes, diluted with 200 ml of THF and cooled to ambienttemperature. 12.7 g (93 mmol) of dry zinc chloride in solution in 20 mlof THF are added and the mixture is stirred for 30 minutes at ambienttemperature. There are then successively added 12.1 g (46 mmol) ofmethyl 6-bromo-2-naphthoate and 300 mg of NiCl₂ /DPPE complex.

The mixture is stirred for 10 hours at ambient temperature. 300 ml ofwater are added and the THF is evaporated. The remainder is extractedwith methylene chloride. The organic phase is dried (MgSO₄), filtered,evaporated and purified by passage through a silica column (eluant:mixture of 50% dichloromethane and 50% hexane). After evaporation of thesolvents, the resulting residue is recrystallized in hexane to give theexpected ester: 11.5 g (72%). Melting point--160° C.

EXAMPLE 27 6-(3-tert.butyl-4-methoxyphenyl)-2-naphthoic acid. Compoundof Formula II wherein R'₂ =tert.butyl, R'₃ =OCH₃ and R'₆ =OH.

In a manner analogous to Example 15, starting with 7.0 g (20 mmol of theester obtained in

Example 26, 6.0 g (90%) of the expected acid are obtained. Meltingpoint: 268° C. EXAMPLE 28 Methyl ester of6-[3-(1,1-dimethyldecyl)-4-methoxy-phenyl]-2-naphthoic acid. Compound ofFormula I wherein R₄ =R₅ =H, R₂ =C(CH₃)₂ C₉ H₁₉, R₃ =OCH₃ and R₁=--COOCH₃

A solution of 16 g (45 mmol) of 2-(1,1-dimethyldecyl)-4-bromo anisole in60 ml of THF is slowly added to of magnesium and a crystal of iodine.The mixture is slightly heated at the beginning of the addition untilthe reaction of formation of the Grignard is initiated. Then theremainder of the solution containing the brominated derivative is addedin a manner to maintain a regular reflux. Once the addition is complete,the mixture is stirred for 30 minutes at 50° C. and then cooled toambient temperature. 7.4 g (54 mmol) of zinc chloride in solution in 50ml of THF are added. The mixture is stirred for 30 minutes at ambienttemperature, 6.6 g (25 mmol) of methyl 6-bromo-2-naphthoate are addedand then 175 mg of NiCl₂ /DPPE complex. The mixture is stirred for 3hours at ambient temperature at which point 250 ml of water are added.The THF is evaporated under reduced pressure and the residue isextracted with dichloromethane, dried and the solvent evaporated. Theresidue is purified by passage through a silica column (eluant: mixtureof 60% dichloromethane and 40% hexane). On evaporation, a solid isobtained which is recrystallized twice in hexane to give the methylester of 6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid:7.05 g (61%). Melting point: 92° C.

EXAMPLE 29 6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl)-2-naphthoic acid.Compound of Formula I wherein R_(4l) =R₅ ═H, R₂ ═C(CH₃)₂ C₉ H₁₉, R₃═OCH₃ and R₁ =COOH.

In a manner analogous to Example 15, starting with 3.6 g of the esterobtained in Example 28, 3 g (87%) of6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid are obtained.Melting point: 180° C.

EXAMPLES OF COMPOSITIONS Example A--Fatty Cream Wherein The ActivePrinciple is in Suspension

    ______________________________________                                        6-[3-(1-adamantyl)-4-methoxy phenyl]-                                                                  0.001    g                                           2-naphthoic acid                                                              A combination of nonionic E/H emulsifiers                                                              25.00    g                                           and a fatty body of mineral origin sold                                       by Goldschmidt under the trade name                                           "Protegin X"                                                                  Petrolatum oil           10.00    g                                           Preservatives, sufficient amount                                              Water, sufficient amount for                                                                           100.00   g                                           ______________________________________                                    

In that example, the active compound can be replaced by the same amountof 6-[3-(1-adamantyl)-4-methoxy phenyl]-1-methyl 2-2-naphthoic acid.

Example B--Skin Cream--A fluid Cream Wherein The Active Principle is inSuspension

    ______________________________________                                        Methyl ester of 6(4-tert.butyl phenyl)-2-                                                              0.02     g                                           naphthoic acid                                                                Sorbitan stearate polyoxyethylenated                                                                   5.00     g                                           with 20 moles of ethylene oxide sold                                          by Atlas under the trade name "Tween 60"                                      Sorbitan monostearate sold by Atlas under                                                              2.00     g                                           the trade name "Span 60"                                                      Cetyl alcohol            5.00     g                                           Triglycerides of capric and caprylic                                                                   10.00    g                                           acids sold by Dynamit Nobel under the                                         trade name "Miglyol 812"                                                      Preservatives, sufficient amount                                              Water, sufficient amount for                                                                           100.00   g                                           ______________________________________                                    

Example C--Gel For The Skin or Scalp Wherein The Active Principle is inSuspension.

    ______________________________________                                        Methyl ester of 6-(4-t.butyl phenyl)-2-                                                                0.10     g                                           naphthoic acid                                                                Ethanol                  20.00    g                                           Hydroxypropyl cellulose, sold by Hercules                                                              2.00     g                                           under the trade name "Klucel HF"                                              Preservative, sufficient amount                                               Water, sufficient amount for                                                                           100.00   g                                           ______________________________________                                    

Example D--Lotion of the Skin

    ______________________________________                                        6-[3-(1-adamantyl)-4-methoxyphenyl]-1-                                                               0.1       g                                            methyl-2-naphthoic acid                                                       Polyethylene glycol 400                                                                              70.0      g                                            Ethanol                29.9      g                                            ______________________________________                                    

In that example, the active compound can be replaced by the same amountof 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.

Example E--Unguent For The Skin

    ______________________________________                                        6-[3-(1-adamantyl)-4-methoxyphenyl]-2-                                                               0.001     g                                            naphthoic acid                                                                Lanolin                50        g                                            Vaseline, sufficient amount for                                                                      100       g                                            ______________________________________                                    

Example F--Oral Composition--0.30 g gelule.

    ______________________________________                                        6-[3-(1-adamantyl)-4-methoxy phenyl]-2-                                                              0.003     g                                            naphthoic acid                                                                Cornstarch             0.060     g                                            Lactose, sufficient amount for                                                                       0.300     g                                            ______________________________________                                    

The resulting powder is packaged in a gelule whose wall is made ofgelatin, TiO₂ and a preservative.

Example G--Capsule Containing 0.400 g Of The Following Suspension

    ______________________________________                                        Ethylamide of 6-[3-(1-adamantyl)-4-methoxy-                                                            0.005   g                                            phenyl]-2-naphthoic acid                                                      Glycerine                0.200   g                                            Sucrose                  0.050   g                                            Polyethylene glycol 400  0.050   g                                            Purified water, sufficient amount for                                                                  0.400   g                                            ______________________________________                                    

This suspension is packaged in a capsule made of gelatin, glycerinetitanium dioxide and water.

What is claimed is:
 1. A process for preparing a compound having theformula ##STR11## comprising coupling, in an anhydrous solvent and inthe presence of, as a reaction catalyst, a transition metal or a complexthereof, a magnesium, lithium or zinc derivative of a compound of theformula ##STR12## with a halogenated naphthalene compound of the formula##STR13## wherein R₁ represents (i) ##STR14## or (ii) --CH₂ OH, R₆represents ##STR15## or OR₇ wherein R₇ represents hydrogen, alkyl having1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' and R"represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl or aresidue of an amino acid or an amino sugar selected from the groupconsisting of glucosamine, galactosamine and mannosamine, or togetherform a heterocycle selected from the group consisting of piperidino,piperazino, morpholino and pyrrolidino,R₂ represents hydrogen, branchedor straight chain alkyl having 1-15 carbon atoms, alkoxy having 1-4carbon atoms or a cycloaliphatic radical, R₃ represents hydrogen,hydroxy, branched or straight chain alkyl having 1-4 carbon atoms,alkoxy having 1-10 carbon atoms, a cycloaliphatic radical selected fromthe group consisting of 1-methyl cyclohexyl and 1-adamantyl, athiocycloaliphatic radical, or --O--Si(CH₃)₂ --R₈ wherein R₈ representslinear or branched lower alkyl, R₄ and R₅, each independently, representhydrogen, lower alkyl, hydroxy or lower acyloxy, and X and Y representCl, Br, F or I.
 2. The process of claim 1 carried out at a temperatureranging from -20° to +30° C.